NM_000541.5:c.301G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000541.5(SAG):c.301G>A(p.Ala101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,605,992 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A101V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0049 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 33 hom. )

Consequence

SAG
NM_000541.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.611

Publications

8 publications found

Variant links:

Genes affected

SAG (HGNC:10521): (S-antigen visual arrestin) Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. S-arrestin, also known as S-antigen, is a major soluble photoreceptor protein that is involved in desensitization of the photoactivated transduction cascade. It is expressed in the retina and the pineal gland and inhibits coupling of rhodopsin to transducin in vitro. Additionally, S-arrestin is highly antigenic, and is capable of inducing experimental autoimmune uveoretinitis. Mutations in this gene have been associated with Oguchi disease, a rare autosomal recessive form of night blindness. [provided by RefSeq, Jul 2008]

SAG Gene-Disease associations (from GenCC):

retinitis pigmentosa 47
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Oguchi disease-1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 96
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinal disorder
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Oguchi disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SAG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00363034).

BP6

Variant 2-233320749-G-A is Benign according to our data. Variant chr2-233320749-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167633.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00495 (753/152244) while in subpopulation AMR AF = 0.0103 (157/15300). AF 95% confidence interval is 0.00895. There are 5 homozygotes in GnomAd4. There are 350 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000541.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAG	NM_000541.5	MANE Select	c.301G>A	p.Ala101Thr	missense	Exon 5 of 16	NP_000532.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SAG	ENST00000409110.6	TSL:5 MANE Select	c.301G>A	p.Ala101Thr	missense	Exon 5 of 16	ENSP00000386444.1
SAG	ENST00000462487.5	TSL:1	n.370G>A		non_coding_transcript_exon	Exon 4 of 5
SAG	ENST00000447536.5	TSL:3	c.301G>A	p.Ala101Thr	missense	Exon 5 of 7	ENSP00000408937.1

Frequencies

GnomAD3 genomes

AF:

0.00494

AC:

751

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00697

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00465

AC:

1088

AN:

234002

AF XY:

0.00479

show subpopulations

Gnomad AFR exome

AF:

0.000789

Gnomad AMR exome

AF:

0.00577

Gnomad ASJ exome

AF:

0.00524

Gnomad EAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.000290

Gnomad NFE exome

AF:

0.00631

Gnomad OTH exome

AF:

0.00974

GnomAD4 exome

AF:

0.00550

AC:

7989

AN:

1453748

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

4015

AN XY:

722358

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

33304

American (AMR)

AF:

0.00652

AC:

283

AN:

43410

Ashkenazi Jewish (ASJ)

AF:

0.00385

AC:

100

AN:

25950

East Asian (EAS)

AF:

0.0000762

AC:

AN:

39380

South Asian (SAS)

AF:

0.00394

AC:

334

AN:

84678

European-Finnish (FIN)

AF:

0.000796

AC:

AN:

52796

Middle Eastern (MID)

AF:

0.0217

AC:

125

AN:

5760

European-Non Finnish (NFE)

AF:

0.00604

AC:

6695

AN:

1108384

Other (OTH)

AF:

0.00602

AC:

362

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

410

820

1230

1640

2050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00495

AC:

753

AN:

152244

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

350

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41548

American (AMR)

AF:

0.0103

AC:

157

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00332

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00697

AC:

474

AN:

68020

Other (OTH)

AF:

0.0109

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00580

Hom.:

Bravo

AF:

0.00605

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00181

AC:

ESP6500EA

AF:

0.00700

AC:

ExAC

AF:

0.00452

AC:

546

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Oguchi disease (1)

Retinal dystrophy (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.039

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.041

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.27

PhyloP100

-0.61

PrimateAI

Benign

0.23

PROVEAN

Benign

0.040

REVEL

Benign

0.082

Sift

Benign

0.39

Sift4G

Benign

0.48

Polyphen

0.016

Vest4

0.085

MVP

0.25

MPC

0.12

ClinPred

0.0046

GERP RS

-0.75

Varity_R

0.049

gMVP

0.18

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over